Prostate cancer is one of the leading causes of morbidity and mortality among men. At the moment, we do not understand the underlying etiology, or why different groups, such as African Americans, have higher rates of disease. Risk factors for prostate cancer have remained elusive and aside from age, having a family history of the disease or African ancestry, until recently, no genetic or non-genetic (i.e., lifestyle) risk factors have been consistently demonstrated to contribute to variation in disease risk in the population. In this application, we propose to undertake a large-scale collaborative effort to uncover genetic predictors of prostate cancer in African American men. For this effort, we have assembled a multi-institutional team of investigators with experience in prostate cancer research in minority populations who are eager and willing to pool resources, specimens and data from their established studies, and to work closely together towards a common goal. To identify genetic factors that contribute to prostate cancer risk in African American men we propose to conduct a well-powered multi-stage genome-wide association study. In stage 1 we will genotype 1,000,000 single nucleotide polymorphisms (SNPs) in 1,500 African American prostate cancer cases and 1,500 controls. In stage 2 we will perform follow-up genotyping of 24,000 SNPs that demonstrate significant main effects and interactions with known risk variants for prostate cancer (e.g. 8q24) in an additional 1,626 African American cases and 1,867 controls. In stage 3, we will further examine genetic associations from stage 1+2 in an additional 1,124 African American cases and 1,163 controls. In this study we will also assess the pan-ethnic effects of the variants identify in the African American scan, by replication testing in 3,900 prostate cancer cases and 4,350 controls of West African, Japanese, Latino and European American ancestry. In this dataset, we will also examine interactions between associated variants, environmental factors (thereby better defining the role of these factors) and disease severity. We expect this work to significantly advance knowledge of the etiology of prostate cancer and racial/ethnic disparities in prostate cancer risk, and to guide the development of future preventive, early detection, prognostic and even therapeutic measures. PUBLIC HEALTH RELEVANCE: The goal of this project is to identify common risk alleles for prostate cancer in African American men. For this effort, we have assembled a multi-institutional team of investigators with experience in prostate cancer research in minority populations who are eager and willing to pool resources, specimens and data from their established studies, and to work closely together towards a common goal. More specifically, we propose to conduct a multi-stage genome-wide association study of prostate cancer, which will include 4,250 African American cases and 4,530 African American male controls. We will examine the pan-ethnic effects of associated variants in other racial/ethnic populations as well as incorporate environment and lifestyle risk factors in association testing to assist in better defining the subgroups of the African American population at greatest risk of developing this common cancer. We expect findings from this work to guide the development of future preventive, early detection and prognostic strategies.